Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria

Fabián Méndez, Alvaro Munoz, Gabriel Carrasquilla, Diana Jurado, Myriam Arévalo-Herrera, Joseph F. Cortese, Christopher V. Plowe

Research output: Contribution to journalArticle

Abstract

Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.

Original languageEnglish (US)
Pages (from-to)230-238
Number of pages9
JournalAmerican Journal of Epidemiology
Volume156
Issue number3
DOIs
StatePublished - Aug 1 2002

Fingerprint

Falciparum Malaria
Tetrahydrofolate Dehydrogenase
Parasites
Mutation
Drug Resistance
Malaria
Dihydropteroate Synthase
Colombia
Plasmodium falciparum
pyrimethamine drug combination fanasil
Codon
Pressure
Mortality
Infection
Pharmaceutical Preparations

Keywords

  • Dihydropteroate synthase
  • Drug resistance
  • Malaria
  • Plasmodium falciparum
  • Pyrimethamine
  • Sulfadoxine

ASJC Scopus subject areas

  • Epidemiology

Cite this

Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria. / Méndez, Fabián; Munoz, Alvaro; Carrasquilla, Gabriel; Jurado, Diana; Arévalo-Herrera, Myriam; Cortese, Joseph F.; Plowe, Christopher V.

In: American Journal of Epidemiology, Vol. 156, No. 3, 01.08.2002, p. 230-238.

Research output: Contribution to journalArticle

Méndez, Fabián ; Munoz, Alvaro ; Carrasquilla, Gabriel ; Jurado, Diana ; Arévalo-Herrera, Myriam ; Cortese, Joseph F. ; Plowe, Christopher V. / Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria. In: American Journal of Epidemiology. 2002 ; Vol. 156, No. 3. pp. 230-238.
@article{881269c299784422904d95fb82f29ddb,
title = "Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria",
abstract = "Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7{\%}), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.",
keywords = "Dihydropteroate synthase, Drug resistance, Malaria, Plasmodium falciparum, Pyrimethamine, Sulfadoxine",
author = "Fabi{\'a}n M{\'e}ndez and Alvaro Munoz and Gabriel Carrasquilla and Diana Jurado and Myriam Ar{\'e}valo-Herrera and Cortese, {Joseph F.} and Plowe, {Christopher V.}",
year = "2002",
month = "8",
day = "1",
doi = "10.1093/aje/kwf030",
language = "English (US)",
volume = "156",
pages = "230--238",
journal = "American Journal of Epidemiology",
issn = "0002-9262",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent transmission potential in falciparum malaria

AU - Méndez, Fabián

AU - Munoz, Alvaro

AU - Carrasquilla, Gabriel

AU - Jurado, Diana

AU - Arévalo-Herrera, Myriam

AU - Cortese, Joseph F.

AU - Plowe, Christopher V.

PY - 2002/8/1

Y1 - 2002/8/1

N2 - Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.

AB - Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.

KW - Dihydropteroate synthase

KW - Drug resistance

KW - Malaria

KW - Plasmodium falciparum

KW - Pyrimethamine

KW - Sulfadoxine

UR - http://www.scopus.com/inward/record.url?scp=0036681854&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036681854&partnerID=8YFLogxK

U2 - 10.1093/aje/kwf030

DO - 10.1093/aje/kwf030

M3 - Article

C2 - 12142257

AN - SCOPUS:0036681854

VL - 156

SP - 230

EP - 238

JO - American Journal of Epidemiology

JF - American Journal of Epidemiology

SN - 0002-9262

IS - 3

ER -